GABRA2 and the Pharmacokinetics of Risk for Alcoholism Hypothesis: An individual's genotype at the GABRA2 gene influences the human brain's initial and adaptive responses to alcohol. This genotypic effect is modulated by a family history of alcoholism, and together these effects contribute to a differential risk for alcoholism. The long term goal of this project is to elucidate factors related to the brain's response to alcohol that place some individuals at greater risk for alcoholism and alcohol-related problems. In the future, assays could be developed to identify high-risk individuals and interventions could be initiated earlier to decrease the risk of future alcohol dependence. In the current grant cycle, our methods for prescribing the time-course of breath alcohol concentration (BrAC) were applied to detect an association between a family history of alcohol dependence and (a) changes in the brain's response to alcohol following a week of abstinence, and (b) brain sensitivity to the rate of change of alcohol exposure. Recently, GABRA2 genotype has been shown to be a risk factor for alcohol dependence, and research suggests a GABRA2 effect in the brain's response to alcohol. Thus, we propose to employ BrAC "clamping" methods to study the effects of variation in GABRA2 on the brain's responses to alcohol in the context of a family history of alcoholism and other factors associated with greater risk for alcoholism. BrAC clamping eliminates the experimental variance associated with oral alcohol administration and achieves the same, constant brain exposure for all subjects. We will use the clamping method to examine the brain's electrophysiological, eye-movement, behavioral, and subjective responses to alcohol as potential alcohol-related endophenotypes of risk. To explore a possible mechanism of genetic influence, we will employ fMRI in the same subjects to examine the effect of GABRA2 genotype and a family history of alcoholism on frontal lobe activity during 2 motor disinhibition tasks while alcohol exposure is clamped. We will initiate longitudinal, periodic assessment of all subjects for symptoms of alcohol use disorders in order to eventually validate the association of genotype with alcohol-related endophenotypes of risk. Overall, we expect that the influences of the GABRA2 high-risk genotype on responses to alcohol will be more apparent in subjects with a positive family history of alcoholism, and will accelerate the onset of alcohol-related problems.